The proposed research aims to generate a comprehensive understanding on the role endocannabinoid (eC) signaling that plays a role in decidualization, a critical step for normal placentation. Studies are aimed at revealing the impact of unbalanced eC signaling via cannabinoid receptor CB1 in decidualization and female fertility. Our results will help draw public attention to potential adverse effects of excessive consumption of street drugs or marijuana on the reproductive health of women of childbearing age. In addition, the proposed research will allow us to explore the functional role of CB1 receptor expression in the uterine luminal epithelium (LE) that directs stromal cell decidualization, and provide a model system to study the molecular nature of the epithelial-stromal interaction in decidualization and impact of dysregulated eC signaling in this process. We propose that an optimal eC-CB1 signaling in the LE is crucial to decidualization following blastocyst attachment with the LE, an aberrant signaling of which will disrupts this process and compromise pregnancy outcome. Our specific aims are to study in mice to test these hypotheses: (1) that eC-CB1 signaling has a major role in regulating stromal cell decidualization with the initiation of embryo implantation. Using mice deleted of Cnr1 (CB1 receptor) or Faah (eC degrading enzyme) and physiological approaches, we will determine if silenced or elevated eC signaling alters decidual response. The results will tell us whether silencing or amplifying eC signaling differently affects decidualization, and whether compromised decidualization affects late pregnancy events, and (2) that intersection of eC-CB1 signaling with other signaling pathways is critical for LE-stromal interactions to initiate the decidualization process. We will pharmacologically block or stimulate eC-CB1 signaling in WT mice to see whether decidualization status changes due to an acute blockage or activation of eC-CB1 signaling. Second, we will assess the interaction of eC signaling with other critical signaling in the LE with respect to decidualization. We will then identify downstream signaling targets emanating from the LE to the stoma by in situ proteomics, and microarray analysis under altered eC-CB1 signaling. This will tell us if epithelial eC signaling is molecularly linked to other signaling pathways relevant to decidualization. The proposed research is aimed at determining the role of cannabinoid/eC signaling in female reproduction relevant to women's reproductive health.